Alzheimer's disease (AD) is characterized by the presence of amyloid plaques and intracellular tau tangles in the brain. Amyloid plaques are composed of a core of beta amyloid (Abeta) which is derived by the proteolytic processing of the amyloid precursor protein (APP). Mutations found in APP that affect the processing the precursor protein into Abeta are associated with the development of familial AD. This circumstantial evidence strongly suggests that Abeta accumulation and/or deposition causes AD (at least in patients with APP mutations) and that modulation of Abeta levels or deposited Abeta may allow therapeutic intervention against the disease. The best animal model in which to study the deposition of amyloid is a transgenic mouse that over-expresses both mutant presenilin-l (PSl) and APP. This line of animal form amyloid deposits by 12 weeks of age. Since mutant PSl elevates Abeta levels in the APP mouse, switching off PSl expression would be expected to reduce Abeta levels. Our overall aim is to investigate whether reducing Abeta levels by switching off Psl after deposits have formed can lead to resolution of the plaques in doubly transgenic tet-PS1/APP mouse model. To do this, we wish to generate a transgenic mouse that constitutively expresses mutant PSl which can be switched off after administration of the tetracycline analogue, doxycycline. Having achieved this, we will seek further funding to cross tet-PSl with APP mice for the study of amyloid stability.